In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active compound.
Further, in the manufacture of oral drug compositions, it is important that a reliable and reproducible plasma concentration profile of drug is provided following administration to a patient. This is of particular importance in the manufacture of compositions comprising anti-thrombotic agents.
Chemical stability, solid state stability and “shelf life” of the active ingredients are also very important factors. The drug substance, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
Moreover, it is also important to be able to provide drug in a form which is as chemically pure as possible.
Amorphous materials may present problems in this regard. For example, such materials are typically difficult to handle and to formulate, provide for unreliable solubility, and are often found to be unstable and chemically impure.
The skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.
Thus, in the manufacture of commercially viable, and pharmaceutically acceptable, drug compositions, it is important, wherever possible, to provide drug in a substantially crystalline, and stable, form.
It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound, either as such or in the form of a salt, will be. This can only be determined empirically.
International patent application WO 02/44145 discloses a number of compounds, which have been found to be useful as thrombin inhibitors or prodrugs of thrombin inhibitors, which thrombin inhibitors are of the general formula I
(wherein Ra, R1, R2, Y and R3 have meanings given in the description of WO 02/44145) and pharmaceutically-acceptable derivatives (including prodrugs) thereof.
WO 02/44145 also specifically discloses the compounds Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)-Aze-Pab(OMe), (referred to hereinafter as Compound A), wherein Aze represents (S)-azetidine-2-carboxylate and Pab represents para-amidinobenzylamino and Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)-Aze-Pab(OH) (referred to hereinafter as Compound B).

A process for the synthesis of Compounds A and B is described in the Examples of WO 02/44145, but Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)-Aze-Pab(OMe) and Ph(3-Cl)(5-OCHF2)—(R)CH(OH)C(O)-Aze-Pab(OH) in crystalline form are not disclosed.
Compounds A and B are metabolised following oral and/or parenteral administration to the corresponding free amidine compound (Compound C), which has been found to be an inhibitor of thrombin (see WO 02/44145, the relevant disclosure in which is hereby incorporated by reference).

International patent application WO 03/101957 provides crystalline pharmaceutically-acceptable acid addition salts, such as ethanesulfonic acid, n-propanesulfonic acid, n-butane sulfonic acid and benzenesulfonic acid salts, of compounds such as Compound A.
However, there remains a need to find crystalline forms of such active compounds which are not in the form of salts. Such free-base crystalline forms allow formulations to be prepared without the requirement for a counter ion (which, for example, contributes “non-therapeutic” weight to the final formulation). For example, using the free base of compound A instead of the benzenesulfonic acid salt allows approximately a 30% decrease in weight, with a corresponding smaller tablet size.